Yeast Genetics for Delineating Bax/Bcl Pathway of Cell Death Regulation

摘要

Defects in the regulation of programmed cell death (apoptosis) play an important role in the pathogenesis of breast cancer, allowing neoplastic cells to survive far longer than their normal counterparts, and thus providing a mechanism for clonal expansion independent of increased cell division. Moreover, failures in normal apoptosis pathways contribute to carcinogenesis by creating a permissive environment for genetic instability and accumulation of gene mutations, promoting resistance to immune-based destruction, allowing disobeyance of cell cycle checkpoints which would normally induce apoptosis, facilitating growth factor/hormone-independent cell survival, allowing cell survival when detached from extracellular matrix during metastasis, reducing dependence on oxygen and nutrients, and conferring resistance to cytotoxic anticancer drugs and radiation. We discovered that expression of the proapoptosis gene BAX is lost in one-third of breast cancers, correlating with poor responses to chemotherapy and shorter survival for patients with metastatic disease. We also found that BAX gene transfer induced cell death not only in breast cancer cells but also yeast. Using yeast genetics approaches, we screened tumor cDNA libraries for suppressors of Bax, resulting in the discovery of a novel human Bax suppressor, BI-1. This anti apoptotic protein thus becomes a new potential drug-discovery target for inducing apoptosis in cancers.